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Sex-Specific Microglia State in the Neuroligin-4 Knock-Out Mouse Model of Autism Spectrum Disorder

ABSTRACT: Neuroligin-4 (NL4) loss-of-function mutations are strongly associated with monogenic heritable abnormalities linked with Autism Spectrum Disorder (ASD). NL4 mutation in mice causes ASD related alterations in both synaptic and behavioral phenotypes. Since microglia closely regulate synaptic development and are implicated as key players in ASD development and progression, we here studied microglial properties in the NL4-knock-out (NL4-/-) mouse model. We show that loss of NL4 caused altered behavior and impaired hippocampal gamma oscillations predominantly in male mice. In parallel, microglial density, morphology, and response to injury specifically in the CA3 region of the hippocampus were altered in NL4-/- males only. A transcriptomic and proteomic analysis revealed strong sexual dimorphism on molecular alterations in microglia of NL4-/-. Together, these results indicate that loss of NL4 affects not only neuronal network activity and behavior, but also changes the phenotype of microglia in a sex by genotype interaction .

ORGANISM(S): Mus musculus

PROVIDER: GSE185419 | GEO | 2021/10/09

REPOSITORIES: GEO

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Sex-Specific Microglia Defects in the Neuroligin-4 Knock-Out Mouse Model of Autism Spectrum Disorder

Project description:Neuroligin-4 (NL4) loss-of-function mutations are strongly associated with monogenic heritable abnormalities linked with Autism Spectrum Disorder (ASD). NL4 mutation in mice causes ASD related alterations in both, the synaptic and behavioral phenotype. Since microglia closely regulate synaptic development and are implicated as key players in ASD development and progression, we here studied microglial properties in the NL4-/- mouse model. We show that loss of NL4 caused altered behavior and impaired hippocampal gamma oscillations predominantly in male mice. In parallel, microglial density, morphology, and response to injury specifically in the CA3 region of the hippocampus were altered in NL4-deficient males only. A transcriptomic and proteomic analysis revealed a strong impact of sexual dimorphism on molecular alterations in microglia of NL4-deficient compared to wildtype mice. Estrogen application in male NL4-/- animals partially restored the impaired social behavior and the altered microglial phenotype. Together, these results indicate that loss of NL4 affects not only neuronal network activity and behavior, but changes in addition the phenotype of microglia in a sex-specific manner that could be targeted by estrogen treatment.

2023-10-24 | PXD024325 | Pride

Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons

Project description:The autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin-4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change of function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.

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Modeling Synaptic Mechanisms of Autism-associated Neuroligin-3 R451C Mutation Using Human Neurons

Project description:Synaptic dysfunction represents a key pathophysiology in neurodevelopmental disorders such as autism spectrum disorder (ASD). Rare mutation R451C in human Neuroligin 3 (NLGN3, encoded by X-linked gene NLGN3), a cell adhesion molecule essential for synapse formation, has been linked to ASD. Despite success in recapitulating the social interaction behavioral deficits and the underlying synaptic abnormalities in mouse model, the impact of NLGN3 R451C on the human neuronal system remains elusive. Here, we generated isogenic knock-in human pluripotent stem cell lines harboring NLGN3 R451C allele and examined its impact on synaptic transmission. Analysis of co-cultured excitatory and inhibitory induced neurons (iNs) with mutation revealed an augmentation in excitatory synaptic strength comparing to isogenic control, but not in inhibitory synaptic transmission. Consistently, the augmentation in excitatory transmission was confirmed in iNs transplanted into mouse forebrain. Using single-cell RNA seq on co-cultured excitatory and inhibitory iNs, we identified differential expression genes (DEGs) and found NLGN3 R451C alters gene networks associated with synaptic transmission. Gene ontology and enrichment analysis revealed convergent gene networks associated with ASD and other mental disorders. Our finding suggests that the NLGN3 R451C mutation could preferentially impact excitatory neurons, which causes overall network properties changes and excitation-inhibition imbalance related to mental disorders.

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Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons

Project description:Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons

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Neuroligin 3 Splice Isoforms Shape Mouse Hippocampal Inhibitory Synaptic Function

Project description:Synapse formation is a dynamic process essential for neuronal circuit development and maturation. At the synaptic cleft, trans-synaptic protein-protein interactions constitute major biological determinants of proper synapse efficacy. The balance of excitatory and inhibitory synaptic transmission (E-I balance) stabilizes synaptic activity and its dysregulation has been implicated in neurodevelopmental disorders including autism spectrum disorders. However, the molecular mechanisms underlying E-I balance remains to be elucidated. Here, we investigate Neuroligin (Nlgn) genes which encode a family of postsynaptic adhesion molecules that shape excitatory and inhibitory synaptic function. We identified that NLGN3 protein differentially regulates inhibitory synaptic transmission in a splice isoform-dependent manner in hippocampal CA1 synapses. Distinct subcellular localization patterns of NLGN3 isoforms contribute to the functional differences observed among splice variants. Finally, our single-cell sequencing analysis reveals that Nlgn1 and Nlgn3 are the major Nlgn genes and that Nlgn splice isoforms are highly diverse in CA1 pyramidal neurons.

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Neuroligin 3 Splice Isoforms Shape Mouse Hippocampal Inhibitory Synaptic Function

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Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system

Project description:INPP5D, which encodes the lipid phosphatase SHIP1, is one of the most common genes associated with the risk of Alzheimer’s disease and is enriched in microglia in the central nervous system. SHIP1 has been found to be highly expressed in plaque-associated microglia. However, how it regulates microglial function and influences brain physiology has been poorly investigated. Here we show that SHIP1 is not only enriched in microglia associated with amyloid beta plaques, but also in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that conditional knockout mice lacking microglial SHIP1 (cKO) display increased complement and synapse loss in the early postnatal brain. Additionally, SHIP1 KO microglia show reduced morphological complexity, altered transcriptional signatures, and abnormal synaptic pruning, which is dependent on the complement system. Single nucleus RNA-sequencing analysis of the entire hippocampus confirmed decreased interaction for synaptic structure-related pathways in both excitatory and inhibitory neurons. Importantly, cKO mice show cognitive defects in adulthood only when microglial SHIP1 is depleted at early postnatal days, but not when depleted at later stages. Finally, using CRISPR/Cas9 we generated human iPSC-derived microglia lacking SHIP1, and validated the increased engulfment of synaptic structures. Altogether, these findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling through the complement system in the early postnatal brain. Disrupting this process has lasting behavioral effects and may provide a link to vulnerability to neurodegeneration.

2024-12-04 | PXD052118 | Pride

Proteomic signature of NPC1 KO microglia

Project description:Niemann-Pick type C (NPC) disease is a rare neurodegenerative disorder mainly caused by autosomal recessive mutations in Npc1 which result in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is one of the prominent pathological features, consequences of NPC1 loss on microglial function and disease outcome remain largely unknown. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in an NPC1-deficient (Npc1-/-) murine model. We demonstrate that microglial defects, including enhanced phagocytosis and impaired lipid trafficking, occur early in the NPC pathological cascade and precede neuronal death. Compromised microglial function during Npc1-/- mouse development is reflected by enhanced synaptic pruning and deficient turnover of myelin. Accumulation of the undigested myelin occurs mainly within multi-vesicular bodies (MVBs) of Npc1-/- microglia and not within lysosomes. This is in agreement with the impairments in recycling of myelin into lipid droplets. Macrophages of NPC patients displayed similar molecular and functional alterations as murine Npc1-/- microglia, strengthening the role of NPC1 in immune homeostasis. Generated ex vivo assays using patient macrophages are novel promising clinical tools to monitor the progression and therapeutic efficacy in NPC patients.

2021-02-09 | PXD019447 | Pride

Proteomic signature of NPC1 KO microglia from conditional KO mice

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Impaired locomotor behavior of C. elegans neuroligin mutants is dependent of the catechol-O-methyltransferase COMT-4

Project description:Neuroligins are neuronal membrane adhesion molecules that have been involved in neuro-psychiatric and neuro-developmental disorders. They interact with neurexins and other specific proteins in the synaptic cleft. The nlg-1 gene of Caenorhabditis elegans encodes NLG-1, an ortholog of human neuroligins. NLG-1 is involved in dopaminergic and serotoninergic signaling that controls the locomotory rate of the nematode. When well fed animals are transferred to a plate with food (bacterial lawn) they reduce the locomotory rate. This behavior, which depends on dopamine, is known as basal slowing response (BSR). Alternatively, food deprived animals when moved to a plate with a bacterial lawn, further decrease their locomotory rate. This behavior, known as enhanced slowing response (ESR) is serotonin dependent. C. elegans nlg-1- deficient mutants are impaired in BSR, ESR and other locomotory behaviors such as gentle touch response. Here we report that nlg-1 mutants upregulate the expression of comt-4 which encodes an enzyme that presumably has catechol-O-methyltransferase activity involved in dopamine degradation. Our study also shows that comt-4(RNAi) in nlg-1-deficient mutants recovers wild type phenotypes of BSR, ESR and gentle touch responses. Based on these results we propose a model for the neuroligin function in modulating the dopamine-dependent locomotory behavior in the nematode.

2018-05-31 | GSE97980 | GEO

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